M.D. Anderson team targets drug-resistant bacteria

Updated 12:19 am, Saturday, February 23, 2013

It's a medical nightmare: going into the hospital for a routine procedure and ending up with a nasty infection.

Such infections are often caused by so-called Gram-negative bacteria, and pose an increasing threat to health care because they are becoming more resistant to antibiotics.

The rising tide of drug-resistant bacteria has pushed scientists to look beyond their primary tool, antibiotics, whose discovery before World War II dramatically improved the safety of surgery and wound care.

Now a pair of cancer researchers believe they have found a new class of weapons, a corkscrew-like peptide, that might take down many of these infectious bacteria.

A peptide is a short chain of organic molecules - the building blocks of life - that is basically a smaller version of a protein, which perform a vast array of jobs in the human cell.

Gram-negative bacteria have been known to cause pneumonia, bloodstream infections and meningitis in health care settings.

"We need to find new solutions," said Dr. Wadih Arap, a medical researcher who designed the new peptide along with his wife, Renata Pasqualini. "We are getting into an era when you see people who get cut while shaving and then they die."

Switching 'hands'

For some time, scientists have known that certain kinds of peptides are effective at penetrating the protective membranes of Gram-negative bacteria that shield them from other medical interventions.

When such peptides are injected into the body, however, its defense systems recognize them as invaders and wipe them out before they can reach the Gram-negative bacteria.

So the challenge Arap and Pasqualini faced was this: Is there a way to engineer a peptide that could bypass the body's defense systems and home in on Gram-negative bacteria?

The trick, it turns out, was changing the "handed­ness" of the corkscrew peptide. The one they were working with was composed of L-amino acids, or left-handed ones. As an experiment they synthesized a similar peptide, but with right-handed amino acids. The result: It was durable inside the human body.

Then they tested it out and the peptide worked marvelously, killing a variety of Gram-negative bacteria strains including E. coli and multiple drug-resistant varieties. They also found that, in laboratory experiments, it did not seem to have a negative effect on other kinds of cells than those they were targeting.

Great potential

The next step, Arap said, is to test further for possible side effects in animal studies of the peptide.

He and Pasqualini also plan to combine the peptide with other drugs that would steer the peptide through the body's bloodstream so that it's targeted specifically to Gram-negative bacteria.

A Rice University biological physicist familiar with the approach, Jose Onuchic, said it has a great potential to fill an unmet need, especially if the M.D. Anderson researchers can devise a clever targeting system.

"We are very interested in combining drugs so that we can be more focused in targeting," he said. "As a research community, we are at the beginning of the journey of understanding how to combine or chaining drugs together to be more specific. Not all bacteria are evil, so the idea of having drugs to kill only what you want is a very, very important thing."